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| | ==Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Bound to a Dibenzoxapine Sulfonamide== | | ==Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Bound to a Dibenzoxapine Sulfonamide== |
| - | <StructureSection load='4lsj' size='340' side='right' caption='[[4lsj]], [[Resolution|resolution]] 2.35Å' scene=''> | + | <StructureSection load='4lsj' size='340' side='right'caption='[[4lsj]], [[Resolution|resolution]] 2.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4lsj]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4LSJ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4lsj]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4LSJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4LSJ FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LSJ:N-{3-[(1Z)-1-(10-METHOXYDIBENZO[B,E]OXEPIN-11(6H)-YLIDENE)PROPYL]PHENYL}METHANESULFONAMIDE'>LSJ</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR3C1, GRL ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LSJ:N-{3-[(1Z)-1-(10-METHOXYDIBENZO[B,E]OXEPIN-11(6H)-YLIDENE)PROPYL]PHENYL}METHANESULFONAMIDE'>LSJ</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4lsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lsj OCA], [http://pdbe.org/4lsj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4lsj RCSB], [http://www.ebi.ac.uk/pdbsum/4lsj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4lsj ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4lsj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4lsj OCA], [https://pdbe.org/4lsj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4lsj RCSB], [https://www.ebi.ac.uk/pdbsum/4lsj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4lsj ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN]] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[http://omim.org/entry/138040 138040]]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref> | + | [https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[https://omim.org/entry/138040 138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN]] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref> | + | [https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | The structural basis of the pharmacology enabling the use of glucocorticoids as reliable treatments for inflammation and autoimmune diseases has been augmented with a new group of glucocorticoid receptor (GR) ligands. Compound 10, the archetype of a new family of dibenzoxepane and dibenzosuberane sulfonamides, is a potent anti-inflammatory agent with selectivity for the GR versus other steroid receptors and a differentiated gene expression profile versus clinical glucocorticoids (lower GR transactivation with comparable transrepression). A stereospecific synthesis of this chiral molecule provides the unique topology needed for biological activity and structural biology. In vivo activity of 10 in acute and chronic models of inflammation is equivalent to prednisolone. The crystal structure of compound 10 within the GR ligand binding domain (LBD) unveils a novel binding conformation distinct from the classic model adopted by cognate ligands. The overall conformation of the GR LBD/10 complex provides a new basis for binding, selectivity, and anti-inflammatory activity and a path for further insights into structure-based ligand design.
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| - | Glucocorticoid receptor modulators informed by crystallography lead to a new rationale for receptor selectivity, function, and implications for structure-based design.,Carson MW, Luz JG, Suen C, Montrose C, Zink R, Ruan X, Cheng C, Cole H, Adrian MD, Kohlman DT, Mabry T, Snyder N, Condon B, Maletic M, Clawson D, Pustilnik A, Coghlan MJ J Med Chem. 2014 Feb 13;57(3):849-60. doi: 10.1021/jm401616g. Epub 2014 Feb 4. PMID:24446728<ref>PMID:24446728</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
| + | |
| - | <div class="pdbe-citations 4lsj" style="background-color:#fffaf0;"></div>
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| | ==See Also== | | ==See Also== |
| - | *[[Glucocorticoid receptor|Glucocorticoid receptor]] | + | *[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Carson, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Clawson, D]] | + | [[Category: Carson M]] |
| - | [[Category: Coghlan, M]]
| + | [[Category: Clawson D]] |
| - | [[Category: Luz, J G]] | + | [[Category: Coghlan M]] |
| - | [[Category: Nuclear hormone receptor]] | + | [[Category: Luz JG]] |
| - | [[Category: Transcription]] | + | |
| Structural highlights
Disease
GCR_HUMAN Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5]
Function
GCR_HUMAN Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6]
See Also
References
- ↑ Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun;87(6):2658-67. PMID:12050230
- ↑ Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb;87(2):680-6. PMID:1704018 doi:http://dx.doi.org/10.1172/JCI115046
- ↑ Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May;91(5):1918-25. PMID:7683692 doi:http://dx.doi.org/10.1172/JCI116410
- ↑ Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep;55(3):363-71. PMID:11589680
- ↑ Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov;86(11):5600-8. PMID:11701741
- ↑ Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Oct;1813(10):1814-21. doi:, 10.1016/j.bbamcr.2011.05.014. Epub 2011 Jun 2. PMID:21664385 doi:10.1016/j.bbamcr.2011.05.014
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